The swallowing of oral medications has long been understood to be problematic for large segments of the population. As many as one third of the United States patient population perceives difficulty in swallowing tablets, capsules, caplets and liquigels. Such difficulties are particularly acute for dysphagics, cancer patents, the elderly, children and other groups (for a good primer on causes of swallowing difficulties, see the Mayo Clinic's online treatment of the issue.
The issue of difficulty with swallowing oral medications involves several problems. One problematic group is the case of a physiologically “normal” patient who perceives difficulties or discomfort in swallowing solid oral medications. Such patients commonly fail to take their medications in a compliant manner. They may not take their medications when recommended, if at all. Frequently, they will crush their tablets, which may defeat time release systems or otherwise adversely alter the desired pharmacokinetic performance of the drug.
The most immediately severe swallowing problem is Actual Esophageal Transit Failure (AETF)—where the tablet actually becomes lodged or sticks in the esophagus. Such failure is generally understood to occur where transit takes thirty seconds or greater but in many cases the transit failure can be total until dissolution. Apart from the failure to deliver the intended medication, many classes of drugs are corrosive to the esophagus. While bisphosphonates, like Fosamax® are commonly understood by practitioners to pose a threat to the esophagus, the medical literature demonstrates that there many classes of drugs that pose a danger—over seventy drugs have been reported to cause esophageal disorders (including inter alia, anti bacterials like doxycycline, tetracycline, clindamycin, etc (see D. Jaspersen, “Drug-induced oesphageal disorders: pathogenesis, incidence, prevention and management,” Drug Saf. 2000; March; 22(3): 237-49)). The typical practitioner is not always familiar with this literature, or simply does not have the knowledge or tools to remedy the issue.
A further problem is posed by the effect of delayed esophageal transit on the timing of peak drug concentration—effective blood levels can be materially delayed by common place transit failure. In a study of twenty patients awaiting cardiac catheterization, 11 patients took an acetaminophen tablet while supine. Transit was delayed in ten of these eleven subjects. The authors observed: “when there was delayed esophageal transit of tablets, the initial absorption of acetaminophen (measured as AUC over the first 60 min) was lower than that after normal esophageal transit of tablets. The peak plasma acetaminophen concentration was also lower and occurred 90 min later when transit was delayed. These kinetic changes decrease the effectiveness of acetaminophen as an analgesic.” See K. S. Channer and C J Roberts, “Effect of Delayed Esophageal Transit on Acetaminophen Absorption” Clinical Pharmacology and Therapeutics 37, 72-76 (1 Jan. 1985).
To date, there have been two primary attempts to address this issue. The first effort has been the invention of rapidly dissolving dosage forms that dissolve in the mouth prior to esophageal transit, most prominently quick dissolve tablets. Various manufacturing methods have been taught and commercialized, including, the Zydis® freeze dried tablet, CIMA's Orasolv® effervescent tablet (now owned by Cephalon), Fuisz Technologies' Flashdose® shearform matrix (invented principally by one of the inventors hereof, Richard C. Fuisz, M.D.), and others. Additionally, other quick dissolving dosage forms have been taught, such as thin film (see the following issued patents on thin film by the current inventors: Fuisz et al. U.S. Pat. Nos. 7,425,292, 7,500,984, 7,666,332, 7,824,588 and 7,897,080)). Sheet and slab dosage forms are another alternative (see e.g. Fuisz US 20100247612A1). Transdermal, vaginal, intra-nasal, buccal, inhalation, intraocular and other systems bypass swallowing entirely. In practice, not all drugs will be suitable for such alternative delivery forms as is manifest in the market share of drug consumption by delivery site.
The second primary attempt to address swallowing difficulties of solid dosage forms has involved the introduction of a superior liquid, to either replace or in some cases augment water during the administration. For example one of the present inventors teaches a liquid with enhanced rheological properties that replaces water during solid dosage form administration and eases esophageal transit by enveloping the solid dosage form in boundary layers of liquid (see one of the current inventor's Fuisz U.S. Pat. No. 6,337,083; see also, Baichwal et al. U.S. Pat. No. 5,670,169; Unger U.S. Pat. No. 6,134,276; Robertson US2007/068012; Fukui C A 2 538 755; and Dairiku et al. EP 0 0873 749). However, the commercial reality has been that companies have been slow to adopt the use of enhanced liquids with the additional distribution and costs issues implied thereby. The solid dosage form—administered with water—remains the gold standard of convenience and cost containment for the administration of most drugs.
The mechanics of esophageal transit for a conventional solid dosage form (e.g. a tablet) have been lightly studied but with provocative implications. For example, a study at the University of Berlin demonstrates that, when administering tablets with water, the volume of water and the position (erect being best) of the patent are key drivers: in the upright position, 45% of capsules were trapped in the oesophagus at a swallowing volume of 5 mL, 7% at 25 mL and 0% at 50 mL. In the supine position, the retention rate was 54% at 5 mL, 28% at 25 mL and 4% at 50 mL (See “Oesophageal transport of solid dosage forms depends on body position, swallowing volume and pharyngeal propulsion velocity,” E. Osmanoglou et al, Neurogastroenterol Motil (2004) 16, 547-556; See also, “Measurement of the Esophageal Transit Time Using a Magnetic Market” Cordova-Fraga et al, Eighth Mexican Symposium On Medical Physics). Thus, the primary finding of Osmanoglu et al. is that upright administration with a high volume of liquid promotes reliable transit. This finding is incorporated in the instructions that accompany bisphosphonates like Fosamax® and Actonel® wherein the patient is instructed to take the tablet with a large amount of water and then remain standing for one hour afterwards. Of course, upright administration with large volumes of water is not practical for many patient populations, and supine or semi supine administration is the reality for many care situations. Additionally, as the population ages, the compliant use of specific volumes of water for swallowing becomes more problematic.
There is a limited body of literature that addresses the relative ease of swallowing of various, conventional solid dosage forms as compared with one another. See Hey et al (“Oesophageal transit of six commonly used tablets and capsules” British Medical Journal Volume 285, Dec. 11, 1982) (concluding that “small tablets are swallowed most easily,” and large tablets should be “oval and not round,” and “capsules of a high density are easier to swallow than lighter ones.”); Drake et al. (“Monitoring esophageal transit of wax-polished Alendronate in healthy postmenopausal women: a new technique for the study of pill transit time” Current Therapeutic Research, 2002 vol. 62 n 2, pp 103-109) (concluding that “oval wax-polished alendronate tablets pass through the esophagus rapidly”); Perkins et al (“Impaired oesophageal transit of capsule versus tablet formulations in the elderly” Gut. 1994 October 35 (10): 1363-1367) (concluding “gelatin capsules showed a clear tendency to remain within the oesphagus of healthy elderly volunteers, while similar sized enteric tablets did not.”); Channer et al (“The effect of size and shape of tablets on their esophageal transit” J Clin Pharmacol. 1986 February; 26(2): 141-6) (concluding “large oval tablets had significantly shorter times than did large round tablets” and “retention of large oval and round tablets in the esophagus occurred in 20% of patients after swallowing while in the standing position. No medium sized tablet was retained, but in 4% of patients, a small tablet remained in the esophagus.”); Perkins et al. (“Esophageal transit and in vivo disintegration of branded risedronate sodium tablets and two generic formulations of alendronic acid tablets” Clinical Therapeutics, Volume 30, Issue 5, May 2008 pp 834-844) (“the branded risedronate tablet has a significantly faster transit time than the 2 generic formulations of alendronate tested.”); and Perkins et al. (“The use of scintigraphy to demonstrate the rapid esophageal transit of the oval film-coated placebo risedronate tablet compared to a round uncoated placebo tablet when administered with minimal volumes of water” Int J. Pharm. 2001 Jul. 17; 222(2): 295-303) (observing “no stasis was observed for the oval film coated placebo risedronate tablet”). Cooker US 2004/0101540 A1 posits that oral dosage forms should be more dense: “it is buoyancy that resists the swallowing process.” (Crooker paragraph 43). Crooker teaches a solid dosage form that will totally submerge or partially submerge in water with an intended vertical positioning alignment. Crooker lacks any in vitro (or in vivo) testing methods, and in fact, we show the opposite to be the case.
However, a review of the foregoing literature demonstrates that it is essentially an ad hoc comparison of one existing solid dosage form's performance with another. There is no real inquiry into first principles of tablet design, nor a suggestion to do so, nor any substantive conclusions concerning the same. Even the question of tablet buoyancy is lightly touched upon and incorrectly at that. For representative samples of the patent art on tableting, see Snowden US 2006/0246136 A1 (Systems, Methods, Apparatuses for Manufacturing Dosage Forms), Berner et al U.S. Pat. No. 6,488,962 (Tablet shapes to enhance gastric retention of swellable controlled-release), Hampton et al. U.S. Pat. No. 5,213,738 (Method for making a capsule-shaped tablet) Lowby U.S. Pat. No. 3,166,476 (Powder Based Tablets).
Despite a lack of understanding of tablet design and swallowing, potential damage from esophageal failure is understood in the scientific literature, if not by the broader medical community. See Jaspersen (cited above), Eckstein et al. (“Iron tablets cause histopathologically distinctive lesions in mucosal biopsies of the stomach and esophagus” Pathology 1996 May 28(2): 142-5); Abid et al (Pill-induced esophageal injury: endoscopic features and clinical outcomes” Endoscopy, 2005 August 27(8): 740-4); Maskins et al “Gastrointestinal side effects of drugs” Expert Opin Drug Saf. 2003 July 2(4): 421-9), etc.
Each of the foregoing references is specifically incorporated as if fully stated herein, together with all references.